Radioactive member and method of making

ABSTRACT

A radioactive member for use in brachytherapy comprising a molded elongate, bioabsorbable carrier material with spaced radioactive sources disposed therein, and methods for the manufacture thereof. The radioactive members may be used in treatment of, for example, prostate cancer.

FIELD OF THE INVENTION

[0001] This invention relates to radiotherapy. More particularly, itrelates to radioactive sources for use in brachytherapy and to methodsfor the preparation of such sources.

BACKGROUND OF THE INVENTION

[0002] Brachytherapy is a general term covering medical treatment whichinvolves the placement of a radioactive source near a diseased tissueand may involve the temporary or permanent implantation or insertion ofa radioactive source into the body of a patient. The radioactive sourceis thereby located in proximity to the area of the body which is beingtreated. This has the advantage that a high dose of radiation may bedelivered to the treatment site with relatively low dosages of radiationto surrounding or intervening healthy tissue.

[0003] Brachytherapy has been proposed for use in the treatment of avariety of conditions, including arthritis and cancer, for examplebreast, brain, liver and ovarian cancer and especially prostate cancerin men (see for example J. C. Blasko et al., The Urological Clinics ofNorth America, 23, 633-650 (1996), and H. Ragde et al., Cancer,80,442-453 (1997)). Prostate cancer is one of the most common forms ofmalignancy in men in the USA, with more than 44,000 deaths in 1995alone. Treatment may involve the temporary implantation of a radioactivesource for a calculated period, followed by its removal. Alternatively,the radioactive source may be permanently implanted in the patient andleft to decay to an inert state over a predictable time. The use oftemporary or permanent implantation depends on the isotope selected andthe duration and intensity of treatment required.

[0004] Permanent implants for prostate treatment comprise radioisotopeswith relatively short half lives and lower energies relative totemporary sources. Examples of permanently implantable sources includeiodine-125 or palladium-103 as the radioisotope. The radioisotope isgenerally encapsulated in a casing such as titanium to form a “seed”which is then implanted. Temporary implants for the treatment ofprostate cancer may involve iridium-192 as the radioisotope.

[0005] Conventional radioactive sources for use in brachytherapy includeso-called seeds, which are sealed containers, for example of titanium,containing the radioisotope within a sealed chamber but permittingradiation to exit through the container/chamber walls (U.S. Pat. Nos.4,323,055 and 3,351,049). Such seeds are only suitable for use withradioisotopes which emit radiation which can penetrate thechamber/container walls. Therefore, such seeds are generally used withradioisotopes which emit γ-radiation or low-energy X-rays, rather thanwith β-emitting radioisotopes.

[0006] For ease of administration of such sources, a number of systemshave been proposed. U.S. Pat. No. 4,815,449 discloses a substantiallynon-deflecting, linear, elongated member for insertion in tumours andmade of a bioabsorbable material in the form of a needle or thin pointedcylinder with a plurality of radioactive seeds disposed therein in apredetermined array.

[0007] U.S. Pat. No. 5,460,592 discloses a method and apparatus fortransporting a radioactive device. The device comprises a flexible,elongated woven or braided bio-absorbable carrier material having spacedradioactive seeds disposed therein. On heating, the carrier materialholding the seeds becomes semi-rigid. A length of the semi-rigid carriermaterial with radioactive seeds disposed therein may then be loaded intoa conventional, hollow metal dispensing needle or applicator cartridgewhich is used to implant the radioactive seeds into or contiguous to thetreatment site, for example a tumour.

[0008] A commercial product consisting of iodine-125 seeds regularlyspaced at between 0.6 and 1.2 cm centre to centre inside a braided,semi-rigid bioabsorbable suture material is available from Medi-PhysicsInc. under the trade name I-125 RAPID Strand™. This product may be usedto treat conditions such as head and neck cancers, including those ofthe mouth, lips and tongue, brain tumours, lung tumours, cervicaltumours, vaginal tumours and prostate cancer.

[0009] One advantage of this type of semi-rigid carrier is that theradioactive seeds are implanted or inserted into a patient with apre-determined known spacing, depending on their separation in thecarrier material. The bioabsorbable material is then slowly absorbedinto the patient's body to leave the spaced seeds in position. Thispredetermined spacing and the semi-rigid nature of the carrier aids aphysician in calculating both the total radiation dose and the doseprofile which will be delivered by the seeds inside a patient's body,and also aids in accurate placement of the seeds. In addition, more thanone seed is implanted at once, so lessening the time taken forimplantation over that required for the placement of individual looseseeds. The risk of seed migration away from the site of implantation isalso reduced (Tapen et al., Int. J. Radiation Oncology Biol. Phys., vol.42(5), pages 1063-1067, 1998).

[0010] Radioactive sources according to U.S. Pat. Nos. 4,815,449 and5,460,592 use as little bioabsorbable material as possible to easeabsorption but the use of such thin or flexible material has a number ofdisadvantages. For example, to ensure that the carrier is rigid enoughto withstand insertion into the patient's tissues, the carrier materialholding the radioactive seeds is stiffened by a heating step during themanufacturing process. However, excessive heat may damage the carriermaterial, and strict control of the heating and cooling process iscritical so as to change the crystalline structure of the carriermaterial sufficiently to cause stiffening but without causing burning.Even when stiffness is maximised within the possibilities existingwithin U.S. Pat. No. 5,460,592, the carrier material is not sufficientlyrigid to fully guard against jamming of the carrier within thedispensing needle or applicator when in clinical use. Jamming of thecarrier within a needle is generally irreversible, so that the needlethen has to be disposed of, taking into account the fact that it is now“hot” due to the presence of radioactive seeds. Any adventitious entryof blood and other body fluids into the needle can cause thebioabsorbable material to swell, and strands of the material to fraywhich also causes jamming of the dispensing needle (Butler et al.,Radiation Oncology Investigations 4:48-49, 1996). It has, therefore,become common practice for physicians to “plug” the needle in order toprevent the entry of body fluids into the needle during administration.However, if the needles are not well plugged, jamming may still occur.Conversely, jamming can be caused by use of too much plug material or aplug of a very stiff nature which is not easily displaced from the tipof the needle.

[0011] The manufacturing process disclosed in U.S. Pat. No. 5,460,592 isalso very labour intensive and does not lend itself easily toautomation. In addition, each carrier must be visually examined afterthe stiffening step to ensure that the seeds are securely retained inthe braided bioabsorbable material.

[0012] Other radioactive members comprise a hollow tube of carriermaterial (see, for example, U.S. Pat. No. 4,815,449 and EP 0,466,681).In such radioactive members, the position of the radioactive sourceswithin the carrier material may be maintained by the contact and/orelasticity of the carrier material or by introducing non-radioactivefillers or “spacers” into the regions between the radioactive sources.However, the manufacture of such radioactive members is non-trivial,requiring three separate materials (carrier material, radioactivesources and non-radioactive spacers) and the careful assembly of thethree in the correct sequence.

[0013] There is, therefore, a need for an improved radioactive memberwhich has one or more of the following advantages: provides a more rigidframework, is more resilient to consumer handling, is easier to use andwhich does not suffer from all the disadvantages of the known sources.Preferably, such an improved radioactive member can be produced using anautomated manufacturing process.

SUMMARY OF THE INVENTION

[0014] Accordingly, in a first aspect of the invention there is provideda radioactive member for use in brachytherapy comprising an elongatebioabsorbable carrier with spaced radioactive sources disposed thereincharacterised in that said radioactive member is formed by molding.

[0015] In a second aspect of the invention there is provided aradioactive member for use in brachytherapy comprising an elongatebioabsorbable carrier with spaced radioactive sources disposed thereincharacterised in that said elongate bioabsorbable carrier is of asubstantially solid composition.

[0016] In a third aspect of the invention there is provided a method formaking a radioactive member in accordance with the first or secondaspect of the invention. Suitably said method comprises the steps of:

[0017] a) providing a mold;

[0018] b) introducing a plurality of radioactive sources into the mold;

[0019] c) introducing liquid bioabsorbable carrier material into themold;

[0020] d) setting the liquid bioabsorbable carrier material; and

[0021] e) removing the set product from the mold.

[0022] In yet another embodiment, the polymer may first be introducedinto the mold and the radioactive sources subsequently introduced intothe molten polymer. The mold then could be opened and the set carriermaterial, forming a strand, removed. In this embodiment, steps b) and c)of the method of the third aspect of the invention would be reversed.

[0023] Accordingly, there is provided a method comprising the steps of:

[0024] a) providing a mold;

[0025] b) introducing liquid bioabsorbable carrier material into themold;

[0026] c) introducing a plurality of radioactive sources into the mold;

[0027] d) setting the liquid bioabsorbable carrier material; and

[0028] e) removing the set product from the mold.

[0029] The present invention still further contemplates providing avented mold in which entrapped air may be forced from the mold cavityupon the introduction of the carrier material.

[0030] The present invention even still further contemplates employing afoaming or blowing method in molding the polymer in which gas bubblesare introduced into the polymer.

BRIEF DESCRIPTION OF THE DRAWINGS

[0031]FIG. 1 shows a radioactive member of the present invention.

[0032]FIG. 2 shows an enlarged view of the radioactive member of FIG. 2,about the section X.

[0033]FIG. 3 shows a mold for producing a radioactive member inaccordance with the present invention.

[0034]FIG. 4 depicts a back mold plate of the present invention.

[0035]FIG. 5 depicts a three plate mold of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0036] Referring to FIG. 1, the present invention provides a radioactivemember 10 for use in brachytherapy. Radioactive member 10 includes anelongate bioabsorbable carrier 12 with spaced radioactive sources 14disposed therein. In one embodiment of the present invention,radioactive member 10 is formed by molding. The present inventionfurther contemplates that carrier 12 is of a substantially solidcomposition.

[0037] With additional reference to FIG. 2, carrier 12 includes aplurality of seed receiving regions 18 and intermediate regions 20.Carrier 12 may define one or more apertures 22 resulting from a moldingprocess of the present invention in which small pins are positioned ateither end of seed receiving regions 18 so as to maintain the locationand alignment of the radioactive sources 14 within carrier 12.

[0038] In one method of the present invention, a two plate vertical moldis constructed to form a radioactive member 10. FIG. 3 depicts a mold 1for producing radioactive members of the present invention. Mold 1includes cooperatively-engageable first and second mold plates 30 and32. Each of mold plates 30 and 32 define an elongate mold cavity, 34 and36, for receiving carrier material and a plurality of radiation sources14. Mold plate 32 includes a plurality of seed positioning pins 38 forpositioning and maintaining the radioactive sources 14 during themolding process. The elongate radioactive sources, or seeds, 14 areplaced into each seed receiving region 20 and held in place the pins 38at the end of each seed. The positions of the pins 38 are also indicatedby the remaining apertures 22 defined by the molded carrier 12 in FIGS.1 and 2. The mold is closed and liquid polymer pumped in at each of theinjection ports 24 defined in mold plate 32 from injection cannisters26. The liquid polymer is set prior to the mold being opened and thestrand (i.e. elongate bioabsorbable carrier) being removed.

[0039] Accordingly, in a first aspect of the invention there is provideda radioactive member for use in brachytherapy comprising an elongatebioabsorbable carrier with spaced radioactive sources disposed thereincharacterised in that the radioactive member is formed by molding.

[0040] In a second aspect of the invention there is provided aradioactive member for use in brachytherapy comprising an elongatebioabsorbable carrier with spaced radioactive sources disposed thereincharacterised in that the elongate bioabsorbable carrier is of asubstantially solid composition.

[0041] By “substantially solid” is meant that the bioabsorbable materialis disposed essentially continuously throughout the radioactive member.Thus, both the wall of the radioactive member, the region containing theseeds and the gaps between the seeds are the same continuous materiali.e. the tubing and spacers are essentially the same single entity withminimal gaps or spaces. Preferably, the radioactive sources will beencapsulated by the bioabsorbable carrier material. This solid nature ofthe radioactive members of the invention helps to ensure that thespacing of the radioactive sources is maintained for at least a shortperiod post-implantation. This helps to ensure proper dosimetry andminimizes source movement, shedding or migration post implantation. Asubstantially solid carrier will have improved rigidity compared withthe “hollow” or braided tubes of conventional carriers.

[0042] The bioabsorbable carrier material may be any non-toxic,bio-compatible, bioabsorbable material or a mixture of such materials.As used herein, a bioabsorbable material is any material of which asubstantial portion will be metabolized within a patient's body andultimately eliminated therefrom. The bioabsorbable material shouldpreferably maintain its integrity once implanted for about 1 to 14 days.Preferably, the carrier material should be fully absorbed by livingtissue over a total of about 70 to 120 days.

[0043] Molding is a method in which a substantially liquid material isintroduced into a mold. When the material sets it takes the shape of themold. The molding process results in a shaped material having asubstantially solid cross section i.e. having material distributeduniformly across its cross section. Thus, particularly preferredbioabsorbable carrier materials which may be used in the radioactivemember of the present invention are those which can have a substantiallyliquid state but can be set by cooling or otherwise to form asubstantially solid carrier. In a particularly preferred embodiment, thebioabsorbable carrier material, once set, will be essentially stiff orrigid.

[0044] In a preferred embodiment of either of the first or secondaspects, the carrier is essentially rigid. By “essentially rigid” it ismeant that the carrier material should have some structural integrityand be resilient enough for its proposed uses. The carrier materialshould be substantially non-deflecting or stiff enough to maintain thespacing between the radioactive sources during implantation of theradioactive member into a patient. A molded radioactive member inaccordance with the present invention can be stiffer than one made froma braided material such as that described in U.S. Pat. No. 5,460,592.The braided material has been found not to be able to be stiffenedenough to prevent jamming according to the scope of physician uses.Jamming may occur when the hollow carrier material used in conventionalcarriers collapses which may be due, for example, to such long axisstrands providing insufficient rigidity or to the overall lack ofmaterial. Moreover, where hollow carriers are used, airspaces betweenthe sources may also lead to collapse due to lack of mechanical strengthwith respect to side compression. The molded carrier material of thepresent invention substantially improves the properties of the finalproduct in these respects.

[0045] Preferably, once in an elongate shape, the bioabsorbable carriermaterial should be easy to cut using for example a scalpel or the like.Alternatively or additionally, the carrier material may possess presetpartially cut or indented points, which facilitate cutting or snappingoff of sections of the radioactive member by the clinician.

[0046] The bioabsorbable carrier material should also preferably have anappreciable shelf life prior to use, without the need for any specialstorage or handling conditions. The carrier material should also besterilisable by any conventional sterilisation method, such as forexample using steam, dry heat, ethylene oxide (EtO Gas), electron-beamor gamma-radiation. A preferred sterilization method is treatment withethylene oxide.

[0047] Suitably the bioabsorbable carrier comprises materials which canbe molded, for example, poly(glycolic acid) (PGA) and poly(-L-lacticacid) (PLLA), polyester amides of glycolic or lactic acids such aspolymers and copolymers of glycolate and lactate, polydioxanone and thelike, or combinations thereof. Such materials are more fully describedin U.S. Pat. No. 5,460,592 which is hereby incorporated by reference.Suitable commercially available polymers include polyglycaprone 25(MONCRYL™), polyglactin 910 (VICRYL™) and polydioanone (PDS II), allavailable from Ethicon, Inc. of New Jersey, U.S.A.

[0048] In a particularly preferred embodiment, the carrier materialcomprises a combination of PLLA (Poly (L-lactide)) and PGA (Poly(glycolide)). Suitably, PLLA and PGA are combined in a ratio of 10/90w/w (10 parts PLLA, 90 parts PGA). In another embodiment, a polymer ofε-caprolactone could be used. Other suitable combinations will berecognised by those skilled in the art.

[0049] Other suitable bioabsorbable polymers and polymer compositionsthat may be used in this invention are described in the followingpatents which are hereby incorporated by reference: U.S. Pat. No.4,052,988 which discloses compositions comprising extruded and orientedfilaments of polymers of p-dioxanone and 1,4-dioxepan-2-one; U.S. Pat.No. 3,839,297 which discloses compositions comprisingpoly[L(−)lactide-co-glycolide] suitable for use as absorbable sutures;U.S. Pat. No. 3,297,033 which discloses the use of compositionscomprising polyglycolide homopolymers as absorbable sutures; U.S. Pat.No. 2,668,162 which discloses compositions comprising high molecularweight polymers of glycolide with lactide; U.S. Pat. No. 2,703,316 whichdiscloses compositions comprising polymers of lactide and copolymers oflactide with glycolide; U.S. Pat. No. 2,758,987 which disclosescompositions comprising optically active homopolymers of L(−) lactidei.e. poly L-Lactide; U.S. Pat. No. 3,636,956 which disclosescompositions of copolymers of L(−) lactide and glycolide having utilityas absorbable sutures; U.S. Pat. No. 4,141,087 which discloses syntheticabsorbable crystalline isomorphic copolyoxylate polymers derived frommixtures of cyclic and linear diols; U.S. Pat. No. 4,441,496 whichdiscloses copolymers of p-dioxanone and 2,5-morpholinediones; U.S. Pat.No. 4,452,973 which discloses poly(glycolic acid)/poly(oxyalkylene) ABAtriblock copolymers; U.S. Pat. No. 4,510,295 which discloses polyestersof substituted benzoic acid, dihydric alcohols, and glycolide and/orlactide; U.S. Pat. No. 4,612,923 which discloses surgical devicesfabricated from synthetic absorbable polymer containing absorbable glassfiller; U.S. Pat. No. 4,646,741 which discloses a surgical fastenercomprising a blend of copolymers of lactide, glycolide, andpoly(p-dioxanone); U.S. Pat. No. 4,741,337 which discloses a surgicalfastener made from a glycolide-rich blend of polymers; U.S. Pat. No.4,916,209 which discloses bioabsorbable semi-crystalline depsipeptidepolymers; U.S. Pat. No. 5,264,540 which discloses bioabsorbable aromaticpolyanhydride polymers; and U.S. Pat. No. 4,689,424 which disclosesradiation sterilizable absorbable polymers of dihydric alcohols.

[0050] Bioabsorbable polymers and polymer compositions are especiallyuseful when they comprise bioabsorbable fillers such as those describedin U.S. Pat. No. 4,473,670 (which is incorporated by reference) whichdiscloses a composition of a bioabsorbable polymer and a fillercomprising a poly(succinimide); and U.S. Pat. No. 5,521,280 (which isincorporated by reference) which discloses bioabsorbable polymers and afiller of finely divided sodium chloride or potassium chloride. Suchfillers can provide increased mechanical stiffness to bioabsorbablepolymers and polymer compositions.

[0051] The radioactive member may be of any suitable cross-section, forexample substantially circular, substantially circular with at least oneflattened surface, or substantially polygonal, for example, square ortriangular.

[0052] As the bioabsorbable carrier material used in the radioactivemember of the present invention is essentially solid, it has a smallersurface area than the equivalent prior art woven or braided materials.It therefore has a lower tendency to swell and cause jamming in thedispensing needle.

[0053] Preferably, a carrier according to the present invention willhave a smooth outer surface, thus limiting friction with the inside ofthe dispensing needle, so making jamming of the carrier within theneedle due to friction between the needle and the surface of the carrierless likely.

[0054] Reduced friction can also be achieved with any cross-sectionhaving at least one flat surface e.g. a substantially circularcross-section flattened at a region on the circumference to give a flatsurface. Suitable carriers may be triangular or substantially polygonalin shape, for example, hexagonal, octagonal, or 12 or 16-sided etc.

[0055] The surface contact between the inner surface of a needle orother delivery device and a carrier of any cross sectional shape can befurther minimized by the provision of suitable surface structures on thecarrier surface which contacts the delivery device. For example, in thecase of a curved carrier surface, surface contact can be reduced byincorporating ridges, spheres or other protrusions in the area of thecarrier surface that contacts the needle or delivery device surface.Preferably, these surface structures comprise biocompatible orbiodegradable carrier material.

[0056] The bioabsorbable carrier can be uniformly or non-uniformlydistributed cross-sectionally around the radioactive sources. Forexample where the sources are substantially cylindrical radioactiveseeds, the shape of the cross-section of the internal surface of thecarrier is, preferably, substantially round. In an alternativeembodiment, the surface is substantially square.

[0057] In one embodiment, the carrier of the radioactive member inaccordance with either of the first or second aspects forms regionscontaining radioactive sources and regions devoid of radioactivesources. In a particularly preferred embodiment, the regions of thecarrier devoid of radioactive sources will be distinguishable from thoseregions containing radioactive sources thus enabling a physician to beable to distinguish between the two regions of the carrier. Thisfacilitates the physician being able to make cuts in the elongatebioabsorbable carrier only in those regions between radioactive sources.It is particularly preferred that the regions of the carrier in whichradioactive sources are disposed should be wider than those regionswhere no radioactive source is present

[0058] In another preferred embodiment, a radioactive member inaccordance with either the first or second aspects of the invention isformed by injection molding.

[0059] Preferably, the carrier material will be visible using ultrasoundimaging techniques i.e. be echogenic. For example, it may comprise soundreflecting particles or bubbles of gas which serve to enhance itsultrasound visibility. Suitable gases include air, nitrogen and carbondioxide. Preferably, the bubbles are at or near the surface of thecarrier.

[0060] The carrier material can be uniformly visible or non-uniformlyvisible by ultrasound. For example, some regions of the carrier may bemore visible by ultrasound than other regions. This can arise due to thepresence of regions where clusters of sound reflecting gas bubbles orparticles reside in a carrier.

[0061] The carrier may additionally or alternatively comprise particleswhich serve to enhance its visibility to ultrasound. Suitable particlesinclude particles of metal (for example titanium or aluminium), glass,silica, iron oxide, sand, clay, plastics such as TEFLON™, porousuniformly-sized non-aggregated particles as described in U.S. Pat. Nos.5,741,522 and 5,776,496 which are hereby incorporated by reference,hollow microcapsules or solid microspheres such as those disclosed inU.S. Pat. No. 5,648,095 which is hereby incorporated by reference, andmicrospheres of a fused sugar, a fused amino acid or of PEG(polyethylene glycol).

[0062] In an alternative embodiment, the radioactive sources themselvesmay be rendered visible to ultrasound (i.e. echogenic) by a suitabletreatment of the container to introduce grooves or other roughening ofthe outer surface of a sealed radioactive source such as a seed. See,for example, WO 00/28554 and WO 00/51136.

[0063] One advantage of using imaging-visible, for exampleultrasound-visible, radioactive members of the invention inbrachytherapy is that the signal and image may be read, measured andanalysed by suitable computer software sufficiently quickly to allow aphysician to plan real-time dosimetry. This is advantageous from aclinical view point for both patient and medical personnel. However, themembers of the invention may be used in processes involving any type ofdosimetry mapping that uses information obtained due to the imagingvisibility of the sources.

[0064] In addition, a physician may use the same imaging technique, forexample ultrasound, already in place during surgery to confirm bothorgan (e.g. prostate) position and size, and source placement. Thiscould enable a physician to calculate if additional sources need to beinserted, for example in situations where the dose pattern needs to berecalculated based on the “real” position of the sources.

[0065] The overall dimensions of the carrier should be such that it willfit inside a dispensing needle or applicator cartridge. For example, ifthe internal diameter of a thin walled 18 gauge needle is 0.102 cm(0.040 inches), then the effective maximum diameter of the carrier ispreferably less than 0.102 cm (0.040 inches), so that it can bedispensed from within such needles.

[0066] Suitably, any conventional radioactive seed may be used as theradioactive source. These include for example the radioactive seedsdisclosed in U.S. Pat. Nos. 5,404,309, 4,784,116, 4,702,228, 4,323,055and 3,351,049 which are hereby incorporated by reference. By “seed” ismeant any sealed container, for example a metal container, containing orencapsulating a radioisotope. Suitable biocompatible container materialsinclude metals or metal alloys such as titanium, gold, platinum andstainless steel; plastics such as polyesters and vinyl polymers, andpolymers of polyurethane, polyethylene and poly(vinyl acetate);composites such as composites of graphite; glass such as matricescomprising silicon oxide, and any other biocompatible material. Titaniumand stainless steel are preferred materials for the containers.

[0067] The radioactive source may also comprise a suitable radioisotopeencapsulated within a polymer or ceramic matrix. Typical sources aresubstantially cylindrical in shape and approximately 4.5 mm long with adiameter of approximately 0.8 mm.

[0068] Accordingly, in a preferred embodiment of first or second aspectof the invention the radioactive sources disposed in the radioactivemember are brachytherapy sources. Suitably, the radioactive sources areradioactive seeds such as, for example, 6711 seeds available fromMedi-Physics, Inc., Arlington Heights, Ill., USA.

[0069] Any radioisotope suitable for use in brachytherapy may be used inthe source. Non-limiting examples include palladium-103, iodine-125,strontium-89, sulphur-35, cesium-131, gold-198, thulium-170,chromium-56, arsenic-73, yttrium-90, phosphorus-32 and mixtures thereof.Especially preferred are palladium-103 and iodine-125. More than onetype of radioisotope may be present in the sources of the invention.

[0070] The sources are preferably disposed linearly along the longestaxis of the elongate carrier material. The orientation of the sourcesrelative to the carrier will depend on the overall size and shape of thecarrier and the sources. If the sources are substantially cylindrical inshape, for example if they are conventional seeds, then they arepreferably orientated with their longitudinal axes parallel to thelongitudinal axis of the elongate carrier itself. Preferably, thesources are regularly spaced, for example at intervals of between 0.6and 1.2 cm, preferably at about 1 cm intervals. A known spacing of about1 cm is preferred if the sources are to be implanted for treatment ofprostate cancer. The number of sources used for any particularapplication will depend on the length of carrier material used.Preferably, the radioactive member is provided as a long strip which canthen be cut or snapped to the desired length for a particularapplication by the medical staff.

[0071] Preferably, all the sources in one carrier will contain the sameradioisotope and/or be of the same radioactive strength. If more thanone type or strength of source is included in one carrier, then thedifferent sources should be arranged in a regular pattern to allowpredictable dosing.

[0072] In a third aspect of the invention there is provided a method formaking a radioactive member in accordance with the first or secondaspect of the invention. Suitably, the method comprises the steps of:

[0073] a) providing a mold;

[0074] b) introducing a plurality of radioactive sources into the mold;

[0075] c) introducing liquid bioabsorbable carrier material into themold;

[0076] d) setting the liquid bioabsorbable carrier material; and

[0077] e) removing the set product from the mold.

[0078] Suitably the mold is elongate i.e. having a length substantiallylonger than the width.

[0079] In a preferred embodiment, the method of the third aspectcomprises injection molding. Injection molding is a common techniqueused for making all manner of plastic parts. It consists of making ametal mold, in which the size and shape of the end product with allother desired characteristics are cut into the metal mold.

[0080] For one method of manufacturing of the present invention, a moldis in two halves, with the bottom half having a cut-out of the bottomcharacteristics of the desired molded product and the top half having acut-out of the top characteristics. The mold also has holes for theliquid “plastic” to enter the mold. The parts of the mold are broughttogether such that that the top and bottom halves are aligned properly,then the liquid plastic is injected in. The plastic is then allowed toset (e.g. by cooling) before the parts of the mold are separated and thehardened plastic part is removed from the mold.

[0081] Suitably, the mold design for producing a radioactive carrier inaccordance with the third aspect of the invention is a three platevertical mold wherein the liquid carrier material is introduced into themold through numerous injection ports. Preferably, the three plate moldfurther comprises a vertical press. Alternative mold designs thatachieve the desired result will be recognised by those skilled in theart.

[0082] Suitably, the carrier material will be introduced in a moltenform. This will typically involve heating the carrier material to itsmelting point prior to injection into the mold. For example,poly(glycolic acid) has a melting point of either 223° C. or 233° C.(Polymer Handbook, J. Brandrup and E. H. Immergut, 3rd Edition, pageVI/61).

[0083] In order to produce a radioactive member in accordance with theinvention, the mold must preferably allow the position of theradioactive sources within the final product to be predetermined andcontrollable. Accordingly, in one embodiment of the third aspect, themold may have a number small of pins protruding inwards towards itscentre position so as to hold radioactive sources at predeterminedpositions in the mold prior to the introduction of the carrier material.Preferably, the small pins are positioned at a spacing which correspondsto the ends of each radioactive source. The mold would be closed withthe radioactive sources held in place, and carrier material pumped, orinjected, in at each of the injection ports. Preferably, the injectionports would be positioned between each radioactive source, or betweenevery other radioactive source, to ensure that the polymer overmolds theseeds.

[0084] In another embodiment of the third aspect, a mold without pinsmay be used. The radioactive sources could be placed into the mold in adefined spacing prior to injection of the liquid carrier material, theliquid carrier material being introduced into the mold in such a way tocause the radioactive sources (e.g. seeds) to roll, fully immersing theradioactive source in the carrier material.

[0085] In still yet another embodiment, the polymer may first beintroduced into the mold and the radioactive sources subsequentlyintroduced into the molten polymer. The mold then could be opened andthe set carrier material, forming a strand, removed. In this embodiment,steps b) and c) of the method of the third aspect of the invention wouldbe reversed.

[0086] Accordingly, there is provided a method comprising the steps of:

[0087] a) providing a mold;

[0088] b) introducing liquid bioabsorbable carrier material into themold;

[0089] c) introducing a plurality of radioactive sources into the mold;

[0090] d) setting the liquid bioabsorbable carrier material; and

[0091] e) removing the set product from the mold.

[0092] A test tool of 1½ seeds was made to confirm the theoreticalfilling and molding having a hollowed out area to receive seeds andovermolding to totally encapsulate the seeds in a strand. The carriermedium material was lactide/glycolide co-polymer (polyglactin 910).

[0093] A second and larger hand loaded insert mold 40 accommodating 10seeds and having injection points for the polymer between each seed wasalso formed. With reference now to FIGS. 4 and 5, mold 40 is athree-plate mold having an elongate base or back mold 42, a seed cavitymold 44, and an encapsulation mold 46. Back mold 42 defines an elongatecavity 48 for receiving the carrier material and forming the lower halfportion of an elongate strand of the radioactive member. Cavity 48 isdefined so as to form intermediate regions 18 and seed receiving regions20 in member 10. Seed cavity mold 44 and encapsulation mold 46 arealternatingly employed to fully mold a radioactive member of the presentinvention.

[0094] Seed cavity mold 44 is first placed in registry over back mold 42to fully enclose cavity 48 for molding the lower half portion of thefinished strand. Seed cavity mold 44 includes a plurality of raisedprotrusions 50, one for each seed 14 to be encapsulated, to extend intocavity 48 for forming a plurality of seed cavities 52, not shown, in thelower half portion of an elongate strand of the radioactive member. Oncethe lower half portion of the carrier material was formed, seed cavitymold 44 is removed and the radioactive sources 14 are placed in the seedcavities 52 in the lower half portion. Encapsulation mold 46 is thenplaced in registry over the lower half portion of the carrier materialin base mold 42. The encapsulation mold defines a cavity 54substantially mirroring cavity 48 for receiving the carrier material andthereby fully encapsulate the radioactive sources.

[0095] The mold plates desirably defines a number an injection ports 58,shown in phantom lines in FIG. 5, for the seed material about theintermediate regions 20 of a finished radioactive member 10. The moldplates also desirably provide mold vents 60 about the seed receivingregions 18 and intermediate regions 20 of a finished radioactive member10. Mold venting is technique known in the molding arts for allowingentrapped air to escape a cavity and to better allow the carriermaterial to flow throughout the mold cavity.

[0096] The present invention further contemplates the use of a foamingor blowing method in molding the polymer. Blowing is accomplished byintroducing gas bubbles into the polymer. Three common methods areemployed to accomplish this are, first, “Whipping” the hot polymermechanically, second, “Inducting” bubbles into the polymer withpressurized gas, and third, employing a “Blowing Agent”. A Blowing Agentis a chemical agent incorporated into the polymer for the purpose ofproducing gas bubbles to form a foam structure as the carrier materialcools that causes bubbles to form in the polymer when heated. Forexample, sodium bicarbonate releases CO₂ gas bubbles upon application ofheat in a mold. The cellular structure of the carrier material can becontrolled by the amount of bicarbonate added or by the size andstructure of the bicarbonate crystals.

[0097] The blowing agent will set up a porous structure much likeStyrofoam and thereby help to insure better mold filling as theviscosity is decreased. Sodium bicarbonate has been employed as ablowing agent for polyglactin 910 polymer to form molded radioactivemembers 10 of the present invention. It was found that the sodiumbicarbonate, or common baking soda, leaves no residue in the polymerwith the exception of CO₂, which is a harmless organic substance.

[0098] Adding a blowing agent to a polymer of the present invention isdesirable for a number of reasons. A blowing agent lowers both themelting temperature of the polymer and the viscosity of the polymer. Ablowing agent makes the polymer more rigid and results in the polymerhaving less surface area on the mold, thereby providing for better moldrelease. As the resulting structure is more porous, there is a betterpolymer yield in that less polymer is required to encapsulate theradioactive sources. The porous structure of the carrier also providesfor a shorter cooling time post injection, which decreases themanufacturing cycle time and allows for more production in a given time.Furthermore, having less polymer in the carrier material provides for ashorter resorbtion rate of the carrier material into the body.

[0099] Further design features of the mold and injection molding processcan readily be understood by those skilled in the art. For example, therate of injection flow is controlled so as to achieve a balanced flowenabling all cavities in the mold to be filled at the approximately thesame time. The position of the injection ports and rate of filling canbe adjusted to ensure a uniform, balanced flow is achieved and that“weld lines” i.e. those regions where adjacent melt-fronts travelling inopposite directions meet and “meld lines” (where two melt fronts flowparallel to each other and create a bond between them) are minimised soas to avoid regions of weakness.

[0100] The pressure of injection will be controlled to ensure filling isachieved with a substantially uniform pressure gradient. Most injectionmolding processes operate at an injection pressure of 100- 150 MPa orless.

[0101] Other features relevant to the design of the molding processinclude temperature distribution, wall-shear stress, shear rate, frozenlayer fraction, ram speed profile etc. Minimising air traps, variationin volumetric shrinkage and sink index is desirable.

[0102] When heated liquid bioabsorbable liquid carrier material is used,setting of the liquid carrier material can be achieved by merelyallowing it to cool. Alternatively, setting can be accelerated by theuse of coolant flowing around the outside of the mold or through themold in small manifolds. Balanced cooling is desirable to ensure thatshrinkage and warpage are minimised.

[0103] The radioactive sources may be positioned in the mold manually orthey may be placed in position using an automated process.

[0104] In a preferred embodiment, the elongate bioabsorbable carrier (or“strand”), once formed, would go through a heated sizing jig to remove“mold marks” and confirm the size of the final diameter. “Mold marks”,or flashing, are little bits of the “plastic” carrier material that areformed at the interface between the two metal mold plates and protrudeout of the mold. There is also sometimes a mold mark left by the portwhere the plastic is introduced.

[0105] In another embodiment, a second heating process at the glasstransition temperature of the carrier material is performed to enhancethe stiffness of the strand. The glass transition temperature isgenerally much lower than the melting point of the carrier material.

[0106] Suitably, surface structures could be formed on the surface ofthe radioactive member formed in accordance with the method of the thirdaspect of the invention. A heated mold or press plate, the surface ofwhich is configured as a negative of the structures, could be applied tothe carrier. This will cause the carrier surface to have a positiveimage, reciprocal to the negative image of the mold. Beads or bumpsproduced on the surface of the carrier can provide reduced contact areaand less friction between the carrier and a needle used as a deliverydevice.

[0107] Preferably the method includes rendering the carrier materialvisible to ultrasound imaging techniques. If the carrier material is apolymer, bubbles of gas may be trapped in the polymer by, for example,blowing bubbles into the polymer prior to injection. Alternatively, thepolymer may be agitated (e.g. by sonication) prior to injection under asuitable gas atmosphere such that bubbles of gas are incorporatedtherein. Suitable gases include air, nitrogen and carbon dioxide.

[0108] Alternatively, the carrier material may be subjected to a gasunder pressure, for example greater than atmospheric pressure,immediately prior to injection such that the gas becomes dissolved intothe material. Upon injection combined with a reduction in the pressureof gas due to warning (such as on injection into an ambient pressure andtemperature environment), the gas will expand to form bubbles in thecarrier material.

[0109] At the end of the manufacturing process, the radioactive membermay be cut to suitable lengths and each length loaded separately into ajig, such as the jig disclosed in U.S. Pat. No. 5,460,592.Alternatively, the member may be wound onto a suitable wheel. The jig orwheel may then be shielded and packaged ready for shipping.

[0110] Optionally, the radioactive member will be shielded for shippingfrom the manufacturing site to the site of use. Preferably, afterpackaging, the product will be sterilized, for example by anyconventional sterilisation procedure such as gamma irradiation orethylene oxide sterilisation. The product can then be shipped from themanufacturer to the site of use as a sterile unit which, once removedfrom the packaging and shielding, is ready for the member to be used.The radioactive member may be packaged in any packaging suitable forshipping.

[0111] A preferred such packaging is a gas-permeable plastic membranesuch as a two-part impermeable and permeable plastic bag which pullsapart. Suitable packaging includes Tyvek™ (DuPont). Such permeablepackaging permits sterilisation of the radioactive member within thepackaging by either ethylene oxide gas (EtO) or autoclaving. Aradioactive member of the present invention supplied sterile, withinsterile integrity packaging is a preferred embodiment of the presentinvention.

[0112] The radioactive members of the invention may be used in thetreatment of a range of conditions including head and neck cancers(including those of the mouth, lips and tongue) brain tumours, lungtumours, cervical tumours, vaginal tumours and prostate cancer. They maybe used as a primary treatment (for example in the treatment of prostatecancer or unresectable tumours) or for treatment of residual diseaseafter excision of the primary tumour. They may be used concurrentlywith, or at the completion of, other treatment modalities, for exampleexternal beam radiation therapy, chemotherapy or hormonal therapy.

[0113] The radioactive members of the invention may be used alone or incombination with individual radioactive sources, for example seeds.

[0114] Thus, as a further aspect of the invention, there is alsoprovided a method of treatment of a condition which is responsive toradiation therapy, for example cancer or arthritis, especially prostatecancer, which comprises the placement of a radioactive member inaccordance with the first or second aspect of the invention at oradjacent the site to be treated within a patient for a sufficient periodof time to deliver a therapeutically effective dose.

[0115] The isotope yttrium-90 may be used for the treatment of pain asit destroys nerve endings. Accordingly, where the radioactive sourcescontain yttrium-90, there is provided a method for the treatment ofpain.

[0116] In another embodiment, there is provided a radioactive member inaccordance with the first or second aspect of the invention for use inthe treatment of cancer or arthritis.

[0117] In a preferred embodiment, the radioactive member may bevisualised using a suitable imaging technique, preferably ultrasoundimaging, in connection with real-time dosimetry equipment.

[0118] The radioactive members of the invention may be administered to apatient by placing a suitable length of carrier into the tip of a hollowneedle and then placing a stylet into the needle. The needle may beinserted into a patient and then pulled back over the stylet leaving thecarrier in place. For methods of administration see, for example, A.van't Riet et al., Int. J. Radiation Oncology Biol. Phys., Vol. 24,pages 555-558, 1992, hereby incorporated by reference.

[0119] While the preferred embodiment of the present invention has beenshown and described, it will be obvious in the art that changes andmodifications may be made without departing from the teachings of theinvention. The matter set forth in the foregoing description andaccompanying drawings is offered by way of illustration only and not asa limitation. The actual scope of the invention is intended to bedefined in the following claims when viewed in their proper perspectivebased on the prior art.

What is claimed is:
 1. A radioactive member for use in brachytherapycomprising an elongate bioabsorbable carrier molded about spacedradioactive sources disposed therein.
 2. A radioactive member as claimedin claim 1 wherein said elongate bioabsorbable carrier is essentiallyrigid.
 3. A radioactive member as claimed in claim 2 wherein saidelongate bioabsorbable carrier is formed from a material selected fromthe group consisting of poly(-L-lactic acid), poly(glycolic acid),polyester amides of glycolic acids, polyester amides of lactic acids,and combinations thereof.
 4. A radioactive member as claimed in claim 3wherein said elongate bioabsorbable carrier comprises a combination ofPLLA (Poly (L-lactide)) and PGA (Poly (glycolide)) having 10 partsPLLA/90 parts PGA w/w.
 5. A radioactive member as claimed in claim 4wherein said elongate bioabsorbable carrier forms regions containingradioactive sources and regions devoid of radioactive sources.
 6. Aradioactive member as claimed in claim 5, wherein said regions of saidelongate bioabsorbable carrier containing radioactive sources are widerthan said regions devoid of radioactive sources.
 7. A radioactive memberas claimed in claim 1, wherein said elongate bioabsorbable carrier isechogenic.
 8. A radioactive member as claimed in claim 1, wherein saidradioactive sources are radioactive seeds.
 9. A radioactive member asclaimed in claim 1, wherein said elongate bioabsorbable carriercomprises a porous structure.
 10. A radioactive member for use inbrachytherapy comprising an elongate bioabsorbable carrier with spacedradioactive sources disposed therein, wherein said elongatebioabsorbable carrier is of a substantially solid composition.
 11. Aradioactive member as claimed in claim 10, wherein said elongatebioabsorbable carrier is essentially rigid.
 12. A radioactive member asclaimed in claim 11, wherein said elongate bioabsorbable carrier isformed from a material selected from the group consisting ofpoly(-L-lactic acid), poly(glycolic acid), polyester amides of glycolicacids, polyester amides of lactic acids, and combinations thereof.
 13. Aradioactive member as claimed in claim 12, wherein said elongatebioabsorbable carrier comprises a combination of PLLA (Poly (L-lactide))and PGA (Poly (glycolide)) having 10 parts PLLA/90 parts PGA w/w.
 14. Aradioactive member as claimed in claim 13, wherein said elongatebioabsorbable carrier forms regions containing radioactive sources andregions devoid of radioactive sources.
 15. A radioactive member asclaimed in claim 14, wherein said regions of said elongate bioabsorbablecarrier containing radioactive sources are wider than said regionsdevoid of radioactive sources.
 16. A radioactive member as claimed inclaim 10, wherein said elongate bioabsorbable carrier is echogenic. 17.A method for making a radioactive member comprising the steps of: a)providing a mold; b) introducing a plurality of radioactive sources intothe mold; c) introducing liquid bioabsorbable carrier material into themold; d) setting the liquid bioabsorbable carrier material; and e)removing the set product from the mold.
 18. A method as claimed in claim17, wherein said introducing step further comprises injecting saidmaterial into said mold.
 19. A method as claimed in claim 18, whereinthe mold has a number of small pins protruding towards its centreposition so as to hold radioactive sources at predetermined positions inthe mold prior to the introduction of the liquid bioabsorbable carriermaterial.
 20. A method as claimed in claim 17, further comprising thestep of introducing a blowing agent into said carrier material.
 21. Amethod as claimed in claim 17, further comprising the step of ventingentrapped air from said mold during said step of introducing liquidbioabsorbable carrier material into the mold.
 22. A method as claimed inclaim 17, wherein said setting step further comprising forming gasbubbles in said carrier material so as to form a porous structure to theset carrier material.
 23. A method of treatment of a condition which isresponsive to radiation therapy which comprises the step of placing aradioactive member as claimed in claim 1 adjacent a site to be treatedwithin a patient for a sufficient period of time to deliver atherapeutically effective dose.
 24. A method as claimed in claim 23wherein the condition is cancer.